Cyclopentanol derivatives and process for the preparation thereof

ABSTRACT

CYCLOPENTANOL DERIVATIVES HAVING THE FORMULA   2-(R-OOC-),3-(Y-A-),4-(HOOC-)CYCLOPENTANOL   WHEREIN A, Y AND R ARE THE SAME AS ABOVE.   2-(R-OOC-),3-(Y-A-),4-(HOOC-)CYCLOPENTANOL   WHEREIN A REPRESENTS A STRAIGHT OR BRANCHED ALYLENE GROUP HAVING 1-8 CARBON ATOMS, Y REPRESENTS CYANO GROUP, CARBAMOYL GROUP OR ANALKOXYCARBONYL GROUP HAVING 1-6 CARBON ATOMS IN THE ALKYL MOIETY AND R REPRESENTS AN ALKYL GROUP HAVING 1-6 CARBON ATOMS WHICH ARE USEFUL AS INTERMEDIATES FOR SYNTHESIS OF PROSTAGLANDIN FLA. THE CYCLOPENTANOL DERIVATIVE MAY BE PREPARED BY REDUCING A CYCLOPENTANONE DERIVATIVE HAVING THE FORMULA

United States Patent 3,806,535 CYCLOPENTANOL DERIVATIVES AND PROCESS FORTHE PREPARATION THEREOF Kiyoshi Sakai, Koichi Kojima, Takashi Yusa, andHamako Katano, Tokyo, Japan, assignors to Sankyo Company Limited, Tokyo,Japan No Drawing. Filed Nov. 28, 1972, Ser. No. 310,133 Claims priority,application Japan, Nov. 29, 1971, 46/96,037, 46/96,038 Int. Cl. C07c61/36, 69/74 U.s.'cl. 260-468 K 4 Claims ABSTRACT OF THE DISCLOSURECyclopentanol derivatives having the formula (POOH wherein A representsa straight or branched alkylene group having 1-8 carbon atoms, Yrepresents cyano group, carbamoyl group or an alkoxycarbonyl grouphaving 1-6 carbon atoms in the alkyl moiety and R represents an alkylgroup having 1-6 carbon atoms which are useful as intermediates forsynthesis of prostaglandin Fla.

The cyclopentanol derivative may be prepared by reducing acyclopentanone derivative having the formula ooorr --A-Y Lo 0 0 Rwherein A, Y and R are the same as above.

This invention relates to novel cyclopentanol derivatives and a processfor the preparation thereof.

More particularly, it relates to cyclopentanol derivatives having theformula goon A Y Patented Apr. 23, 1974 ice oxycarbonyl and the group Rmay be methyl, ethyl, propyl, isopropyl, n butyl, pentyl and hexyl.

A preferred group of the compound provided by the present invention arethose of the Formula I wherein A represents hexamethylene group and Yrepresents an alkoxycarbonyl group having 1-6 carbon atoms in the alkylmoiety, i.e., those having the formula coon ' bb-R GO,

OH lI- l wherein R is the same as above and R represents an alkyl grouphaving 1-6 carbon atoms.

In the above Formulae I and I-a and elsewhere in this specification, abond attached to the cyclopentane nucleus which is in thelat-configuration, i.e., extends below the plane of the cyclopentanering, is represented by a dotted line, and a bond which is in theB-configuration, i.e., extends above the plane of the cyclopentane ring,is represented by a solid line.

The cyelopentanol derivatives having the above Formulae I and I-a areuseful as intermediates used in the 2-formylcyclopentane derivativeshaving the formula manufacture of prostaglandin Flea having hypotensiveand smooth muscle-stimulating activity.

It has 'been described in German patent Olfenlegungsschrift No.2,044,698 that prostaglandin =F lot can be prepared from2-formy1cyclopentane derivatives having the formula 320.. "p Uorrowherein A and Y are the same as above and R represents atetrahydropyranyl group or an alkoxyalkyl group having 1-6 carbon atomsin each alkyl moiety and that the cyclopentane ring can be formed byoxidizing a bicyclopentane derivative prepared by a Diels-Alder reactionof cyclopentadiene with a diene com und. The 2-formylcyclopentanederivatives, however, cannot be stereo-specifically produced in theprior art, that is, the 2-formylcyclopentane derivatives are obtained asa mixture of a stereochemical isomer regarding to the substituents inthe 1-, 2-, 3- and 4-position of the cyclopentane ring.

It is an object of the present invention to provide 2,4-dicarboxycyclopentanol derivatives having the substituents of the sameconfiguration as prostaglandins, i.e., having the substituents of transconfiguration in the 1-2 position, trans configuration in the 2-3position and cis configuration in the 3-4 position and a process for thepreparation thereof.

When the present process is employed as one of steps, there may bestereospecifically obtained prostaglandius.

According to the process of the present invention, the cyclopentanolderivative having the Formula I may 'be prepared by reducing acyclopentanone derivative having the formula coon ' --AY UCOOB whereinA, Y and R are the same as above.

In the process of this invention, when the optical isomer or the racemicmixture of the compound having the Formula II are employed, there may beobtained the corresponding optical isomer or the racemic mixture of thecompound having the Formula I.

The reduction may be preferably carried out by contacting the compound(Ill) with a metal hydride complex in the presence of a solvent or bysubjecting the compound (II) to catalytic reduction.

As the metal hydride complex, there may be preferably employed an alkalimetal hydride complex, for example, sodium boron hydride, potassiumboron hydride and lithium boron hydride and an aluminum hydride complex,for example, aluminum trimethoxylithium hydride, aluminumtri-tert-butoxylithium hydride. It is desirable to employ an excessamount of the metal hydride complex. As the solvent, there may beemployed any inert organic solvent without limitation that would nothave an effect on the reaction.

Preferable examples of such a solvent include alcohols, e.g., methanol,ethanol, ethers, e.g., diethyl ether, dioxane, tetrahydrofuran, diglyme;dialkylformamides, e.g., dimethylformamide.

The reaction temperature is not critical, but it is preferable to carryout the reaction at low temperatures in order to control side reactions,preferably at the temperature ranging from 'l0 C. to room temperature.The reaction period will depend mainly upon the reaction temperature anda kind of the metal hydride complex and may vary from about 5 minutes toone hour. When the reaction is carried out by catalytic reduction, theremay be preferably employed, as the catalyst, platinum catalyst, e.g.,platinum wire, platinum plate, platinum black, spongy platinum, platinumoxide, colloidal platinum. The reaction is usually carried out in thepresence of a solvent. As the solvent, there may be employed any solventwithout limita tion that would not have an effect on the reaction.

Preferable examples of such a solvent include water; alcohols, e.g.,methanol, ethanol, ethylene glycol; ethers, e.g., diethyl ether,dioxane, tetrahydrofuran, diglyme; hydrocarbons, e.g., benzene, toluene,cyclohexane, methylcyclohexane; esters, e.g., ethyl acetate; carboxylicacids, e.g., acetic acid; and dialkylformamides, e.g.,dimethylformamide. The reaction may be carried out under ordinarypressure or increasing pressure. The reaction tempeature is not criticalbut the reaction is preferably carried out at low temperature in orderto control side reactions, preferably at room temperature. The reactionends when the absorption of hydrogen gas ceases.

After completion of the reaction, the desired product may be recoveredfrom the reaction mixture by conventional means. For instance, when themetal hydride is employed, organic acids such as formic acid and aceticacid are added to the reaction mixture in order to decompose thereducing agent and the mixture is made acidic. The mixture is extractedwith an organic solvent and the extract is washed with water and dried.The solvent is distilled off to give the desired product. When thereduction is carried out by catalytic reduction, the reaction mixture isfiltered to remove the catalyst employed and the solvent is distilledoff from the filtrate to give the desired product. The desired productthus obtained may be, if necessary, further purified by conventionalmeans, for example, column chromatography or thin-layer chromatography.

On the present reaction there m y be st sp fi l y obtained thecyclophentanol derivative (I) having the substituents of transconfiguration in the 1-2 position, trans configuration in the 2-3position and cis configuration in the 3-4 position.

The compounds having the above Formula II, employed as startingmaterials, are novel and can be prepared by the process shown in thefollowing reaction schema.

CHzCO CHzC O OCHzPh (III) In the above formulae, A, Y and R are the sameas above and R represents an alkyl group having 1-6 carbon atoms, Phrepresents phenyl group, Hal represents a halogen atom such as chlorineand bromine and the formula represents the formula or a mixture thereof.

Each of the above steps will be illustrated as follows:

The compound (V) may be prepared by contacting the compound (III) withthe compound (IV) in the presence of a base.

Examples of the base include in alkali metals e.g. metallic sodium;metal hydrides e.g. sodium hydride; and thallium compounds, e.g.,thallium hydroxide, methoxythallium. The reaction is usually carried outin the presence of a solvent. As the solvent, there may be employed anysolvent without limitation that would not have an effect on thereaction.

Examples of such a solvent include hydrocarbons, e.g. benzene, tolueneand ethers, e.g., diethyl ether, tetrahydrofuran, dioxane. Thesesolvents are preferably employed especially in anhydrous condition. Thereaction temperature is not critical, but it is preferably from --10 C.to 40 C. The reaction period will depend mainly upon the reactiontemperature and a kind of the base employed and may vary from 30 minutesto 15 hours.

The compound (VII) or the compound (VIII) or a mixture thereof may beprepared by contacting the compound (V) with the compound (VI) in thepresence of a base. As the base, there may be preferably employed astrong base such as alkali metals, e.g., metallic sodium; alkali metalhydroxides, e.g., sodium hydroxide, potassium hydroxide; alkali metalhydrides, e.g., sodium hydride; alkali metal alkoxide, e.g., sodiumtert-butoxide, potassium tert-butoxide, sodium methoxide, potassiumethoxide; alkali metal amides, e.g., sodium amide, potassium amide; andmetal salts of dialkyl sulfoxide, e.g., sodiumor potassium salt ofdimethyl sulfoxide. The reaction is usually carried out in the presenceof a solvent. As the solvent, there may be employed any inert organicsolvent without limitation that would not have an effect on thereaction. Examples of such a solvent include hydrocarbons, e.g.,benzene, toluene, cyclohexane; ethers, e.g., diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran; dialkylformamide, e.g.,dimethylformamide; and dialkyl sulfoxide, e.g., dimethyl sulfoxide. Thereaction temperature is not critical and it is usually from at roomtemperature to a reflux temperature of a solvent employed; The reactionperiod will depend mainly upon the reaction temperature and a kind ofthe base and may vary from about 2 hours to 24 hours.

The compound (IX) may be prepared by contacting the compound (VII) orthe compound (VIII) or a mixture thereof with an acid. As the acid,there may be preferably employed an organic strong acid such astrifluoroacetic acid, monochloroacetic acid, dichloroacetic acid,trichloroacetic acid, benzenesulfonic acid and p-toluene-sulfonic acidand a mineral acid such as hydrochloric acid, perchloric acid, sulfuricacid and phosphoric acid. The reaction may be carried out in thepresence or absence of a solvent, but it is preferable to employ Iasolvent in order to proceed the reaction smoothly. As the solvent, theremay be any solvent without limitation that would not have an effect onthe reaction. Examples of such a solvent include hydrocarbons, e.g.,benzene, toluene, cyclohexane; ethers, e.g., diethyl ether, dimetho-xyethane, dioxane, tetrahydrofuran; dialkylformamides, eg.,dimethylformamide; dialkyl sulfoxides, e.g., dimethyl sulfoxide;hydrocarbon halide, e.g., dichloromethane, trichloromethane, carbontetrachloride aud esters, e.g., ethyl acetate. The reaction temperatureis not critical, but it is usually from C. to room temperature. Thereaction period will depend mainly upon the reaction temperature and akind of the acid and may vary usually from 1 hour to 10 hours.

The compound (X) may be prepared by contacting the compound (IX) with abase. Examples of the base include alkalior alkaline earth metalhydroxides, e.g., sodium hydroxide, potassium hydroxide, calciumhydroxide, barium hydroxide; alkalior alkaline earth metals, e.g.,metallic sodium, -potassium, -calcium, -barium; alkali metal carbonates,e.g., sodium carbonate, potassium carbonate; alkali metal bicarbonates,e.g., sodium bicarbonate, potassium bicarbonate, alkalior alkaline earthmetal acetates, e.g., sodium acetate, potassium acetate, calciumacetate; alkalior alkaline earth metal alkoxides, e.g., sodiummethoxide, potassium ethoxide, calcium ethoxide; and alkali metalfluorides, e.g., sodium fluoride, potassium fluoride. The reaction isusually carried out in the presence of a solvent. As the solvent, theremay be employed without limitation that would not have an effect on thereaction. Examples of such a solvent include ethers, e.g., diethylether, dimethoxyethane, dioxane, tetrahydrofuran; hydrocarbons, e.g.,benzene, toluene, cyclohexane; and alcohols, e.g., methanol, ethanol,ethylene glycol. The reaction temperature is not critical, but thereaction may be preferably carried out at the temperature ranging from-10 C. to 50 C. The reaction period will depend mainly upon the reactiontemperature and a kind of the base employed and may vary from about 30minutes to 10 hours.

Alternatively, the compound (X) may be prepared by contacting thecompound (V) with the compound (XI) in the presence of a strong base.Examples of the base include alkali metals, e.g., metallic sodium,alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide;

alkali metal hydrides, e.g., sodium hydride; alkali metal alkoxide,e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide,potassium ethoxide; alkali metal amides, e.g., sodium amide, potassiumamide; and alkali metal salts of dialkyl sulfoxide, e.g., sodiumorpotassium salt of dimethyl sulfoxide. The reaction is preferably carriedout in the presence of a solvent. As the solvent, there may be employelany inert organic solvent without limitation that would not have aneffect on the reaction. Examples of such a solvent include hydrocarbons,e.g., benzene, toluene cyclohexane; ethers, e.g., diethyl ether,dimethoxymethane, dioxane, tetrahydrofuran; dialkylformamides, e.g.,dimethylformamide; and dial'kyl sulfoxide, e.g., dimethyl sulfoxide. Thereaction temperature is not critical, but the reaction may be preferablycarried out at the temperature ranging from 0 C. to 50 C. The reactionperiod will depend mainly upon the reaction temperature and a kind ofthe base employed and may vary from one hour to 10 hours.

The compound (II) may be prepared by subjecting the compound (X) tocatalytic reduction in the presence of a solvent. As the catalyst whichmay be used in the reaction, there may be preferably employed palladiumcatalyst such as palladium black, palladium oxide, colloidal palladium,anhydrous colloidal palladium, palladium-barium sulfate, palladium oncharcoal, palladium on bariumor strontium carbonate and palladium onsilica gel; rhodium catalyst such as rhodium asbestos and colloidalrhodium; iridium catalyst such as iridium asbestos and colloidaliridium; nickel catalyst such as reduced nickel catalyst, nickel oxidecatalyst, Raney nickel catalyst, Urushibara nickel catalyst and nickelboride catalyst; cobalt catalyst such as Raney cobalt catalyst, reducedcobalt catalyst and Urushibara cobalt catalyst; iron catalyst such asreduced iron catalyst and Raney iron catalyst; copper catalyst such asreduced copper catalyst, copper on carrier and Raney copper catalyst. Asthe solvent, there may be employed any solvent without limitation thatwould not have an effect on the reaction. Preferable examples of such asolvent include water; alcohols, e.g., methanol, ethanol and ethyleneglycol; ethers, e.g., diethyl ether, dioxane and tetrahydrofuran;hydrocarbons, e.g., benzene, toluene, cyclohexane and methylcyclohexane;esters, e.g., ethyl acetate; and carboxylic acids, e.g. acetic acid. Thereaction may be carried out under ordinary pressure or increasingpressure. The reaction temperature is not critical, but the reaction ispreferably carried out at from 0 C. to room temperature. The reactionends when the absorption of hydrogen gas ceases. On the presentreaction, there may be stereospecifically obtained the cyclopentanonederivatives (II) having substituents of trans configuration in the 2-3position and cis configuration in the 3-4 position.

The known 2-formylcyclopentane derivatives (U) can be prepared from thecyclopentanol derivatives (I) by the process shown in the followingreaction schema.

c 0 on go on c OHal Y ..A Y

0 0 OR GO OR K) on on B (1) (XII) (XIII) QH QC OR 30R --AY CODE. 0 0 ORGO OR (XVI) (XV) (XIV) 9 9 z I ...A.

COOR CH OH om om 0R (XVII) (XIX) (XX) --'A-COOH U0 0 OR (XVIII) In theabove formulae, A, Y, R, R and Hal are the same as above, R representsan acyl group of a hydrocarbon carboxylic acid containing 1-12 carbonatoms, R represents an alkyl group having l-6 carbon atoms and Zrepresents Y or carboxyl group.

Each of the above steps will be illustrated as follows:

The compound (XII) may be prepared by contacting the compound (II) witha hydrocarbon carboxylic acid or a halide or anhydride thereof. Thereaction may be carried out in the presence or absence of a solvent.Examples of the carboxylic acid or the halide or anhydride includeacetic acid, propionic acid, benzoic acid, the chloride, bromide 0ranhydride of such an acid. Preferable examples of a solvent includeamines, e.g., pyridine, triethylamine; halogenohydrocarbons, e.g.,chloroform, dichloromethane; ethers, e.g., diethyl ether,tetrahydrofuran, dioxane; hydrocarbons, e.g., benzene, toluene; ethers,e.g., ethyl acetate. The reaction temperature is not critical, butpreferably the reaction may be carried out at the temperature rangingfrom 0 C. to room temperature. The reaction period depends mainly uponthe reaction temperature and a kind of the reagent and may vary fromabout one hour to 24 hours.

The compound (XIII) may be prepared by contacting the compound (XII)with a halogenating agent. As the halogenating agent, there may beemployed dicarboxylic halides, e.g., oxalyl chloride, oxalyl bromide,malsyl chloride, succinyl chloride; phosphorus halides, e.g., phosphorusoxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorustribromide, phosphorus pentachloride, phosphorus pentabromide; thionylhalides, e.g., thionyl chloride, thionyl bromide; a mixture oftriarylphosphine and carbon tetrahalide, e.g., a mixture oftriphenylphosphin and carbon tetrachloride. As a solvent, there may bepreferably employed an inert organic solvent such as ethers, e.g.,diethyl ether, dioxane, tetrahydrofuran; hydrocarbons, e.g., benzene,toluene. The reaction temperature is not critical and usually the rangeof the reaction may be carried out at the temperature ranging from 0 C.to room temperature. The reaction period will depend mainly upon thereaction temperature and a kind of the halogenating agent and may varyfrom about minutes to 5 hours.

The compound (XIV) may be prepared bycontacting the compound (XIII) withan alkylating agent. As the alkylating agent, there may be employedalkyl metal compounds such as dialkylcopperlithium, e.g.,dimethylcopperlithium, diethylcopperlithium; a dialkylcadmium, e.g.,dimethylcadmium, diethylcadmium; an alkyllithium, e.g., ethyllithium; aGrignard reagent, e.g., methylmagnesium bromide, ethylmagnesium iodide.The reaction is carried out in the presence of a solvent. As thesolvent, there may be employed any inert organic solvent withoutlimitation that would not have an effect on the reaction. Preferableexamples of such a solvent include ethers, e.g., diethyl ether,dimethoxyethane dioxane, tetrahydrofuran; hydrocarbons, e.g., benzene,toluene. The reaction temperature is not critical. In case of employingthe dialkylcopperlithium, the alkyllithium or the Grignard reagent, thereaction is desirably carried out at relatively low temperature,preferably at the temperature ranging from C. to room temperature, inorder to control side reactions. The reaction period will depend mainlyupon the reaction temperature and a kind of the alkylating agent and mayvary from about 5 minutes to 10 hours.

In case of employing the dialkylcadmium as the reagent, the reaction iscarried out at relatively high temperatures, usually at the temperatureranging from room temperature to a reflux temperature of a solventemployed. The reaction period will depend mainly upon the reactiontemperature and may vary from about 30 minutes to 5 hours.

The compound (XV) may be prepared by contacting the compound (XVI) withperoxides. As the peroxides, there may be preferably employed organicperoxides, for example, performic acid, peracetic acid, perpropionicacid, perluric acid, percomphoric acid, pertrifluoroacetic acid,perbenzoic acid, m-chloroperbenzoic acid and monoperphthalic acid andhydrogen peroxide. The reaction may be carried out in the presence orabsence of a solvent. It is preferable to employ a solvent in order toproceed the reaction smoothly. As a solvent, there may be employed anysolvent without limitation that would not have an effect on thereaction. Preferable examples of such a solvent includehalogenohydrocarbons, e.g., chloroform, dichloromethane; ethers, e.g.,dioxane, tetrahydrofuran; esters, e.g., ethyl acetate. The reactiontemperature is not critical, but the reaction is desirably carried outat low temperatures, preferably at the temperature ranging from -l0 C.to room temperature, in order to control side reactions. The reactionperiod will depend mainly upon the reaction temperature and a kind ofthe peroxides and may vary from about 10 minutes to 10 hours.

The compound (XVI) may be prepared by contacting the compound (XV) witha base. As the base, there may be employed alkalior alkaline earthhydroxides, e.g., sodium hydroxide, potassium hydroxide, calciumhydroxide; alkali metal carbonates, e.g., sodium carbonate, potassiumcarbonate; alkali metal bicarbonate, e.g., sodium bicarbonate, potassiumbicarbonate; alkalior alkaline earth metal alkoxides, e.g., sodiummethoxide, potassium ethoxide, calcium ethoxide; organic amines, e.g.,trimethylamine, triethylamine, pyridine, piperidine.

The reaction is preferably carried out in the presence of a solvent. Asthe solvent, there may be employed water; alcohols, e.g., methanol,ethanol; ethers, e.g., dioxane, tetrahydrofuran; dialkylformamides,e.g., dimethylformamide; dialkyl sulfoxides, e.g., dimethyl sulfoxide;and a mixture of water and such an organic solvent. The reactiontemperature is not critical, but the reaction may be preferably carriedout at the temperature ranging from room temperature to 70 C. Thereaction period will depend mainly upon the reaction temperature and akind of the base employed and may vary from about 30 minutes to 3 hours.

The compound (XVII) may be prepared by contacting the compound (XVI)with tetrahydropyran or alkoxyalkyl halides. When the tetrahydropyransare employed as a reactant, the reaction is carried out in the presenceof a small amount of acids.

Examples of the tetrahydropyrans include tetrahydropyran,tetrahydrothiopyran, 4-methoxytetrahydropyran. As the acids, there maybe employed a mineral acid, for example, acid, e.g., hydrochloric acid,hydrobromic acid and an organic acid, for example, picric acid,trifiuoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid. Thereaction may be carried out in the presence or absence of a solvent. Itis preferable to employ a solvent in order to proceed the reactionsmoothly. As the solvent, there may be employed any inert Organicsolvent without limitation that would not have an effect on thereaction. Examples of such a solvent include halogenohydrocarbons, e.g.,chloroform, dichloromethane and nitriles, e.g., acetonitrite.

When the alkoxyalkyl halides are employed as a reactant, the reaction iscarried out in the presence of a base. As the base, there may beemployed alkali metal hydrides, e.g., sodium hydride, potassium hydride,lithium hydride, alkali metal amides, e.g., sodium amide, potassiumamide, alkali metal alkoxides, e.g., sodium methoxide, potassiumethoxide and dialkylsulfoxide metal salt, e.g., dimethylsulfoxide sodiumsalt, dimethylsulfoxide potassium salt.

The reaction may be carried out in the presence or absence of a solvent.It is preferable to employ a solvent in order to proceed the reactionsmoothly. As the solvent, there may be employed any inert organicsolvent without limitation that would not have an effect on thereaction. Examples of such a solvent include ethers, e.g.,tetrahydrofuran, dioxane, diethyl ether; hydrocarbons, e.g., benzene,toluene, cyclohexane; dialkylf'ormamide, e.g., dimethylformamide; anddialkylsulfoxide, e.g., dimethyl sulfoxide. The reaction temperature isnot critical, but the reaction may be preferably carried out at thetemperature ranging from C. to room temperature. The reaction periodwill depend mainly upon the reaction temperature and a kind of thereactant and may vary from about one hour to 24 hours.

The compound (XVIII) may be prepared by contacting the compound (XVII)with a base. As the base, there may be preferably employed alkalioralkaline earth hydroxides, e.g., sodium hydroxide, potassium hydroxide,calcium hydroxide; alkali metal carbonates, e.g., sodium carbonatepotassium carbonate; alkali metal bicarbonate; e.g., sodium bicarbonatepotassium bicarbonate; alkalior alkaline earth metal alkoxides, e.g.,sodium methoxide, potassium ethoxide, calcium ethoxide. The reaction ispreferably carried out in the presence of a solvent. As the solvent,there may be employed water, alcohols, e.g.,

methanol, ethanol; ethers, e.g., dioxane, tetrahydrofuran;

dialkylformamides, e.g., dimethylformamide; dialkyl sulfoxides e.g.,dimethyl sulfoxide; and a mixture of water and such an organic solvent.The reaction temperature is not critical, but the reaction may bepreferably carried out at the temperature ranging from room temperatureto reflux temperature of the solvent. The reaction period will dependmainly upon the reaction temperature and a kind of the base employed andmay vary from about 30 minutes to 10 hours.

The compound (XIX) may be prepared by reducing the compound (XVII) or(XVIII) with a reducing agent. As the reducing agent, there may beemployed a metal hydride complex, for example, sodium boron hydride,potassium boron hydride, lithium boron hydride, lithium aluminum hydrideand tri-tert-butoxy lithium aluminum. The reaction is preferably carriedout in the presence of a solvent. As the solvent, there may be employedany inert organic solvent without limitation that would not have aneffect on the reaction. Examples of such a solvent include alcohols,e.g., methanol, ethanol; ethers, e.g., tetrahydrofuran, dioxane. Thereaction temperature is not critical, but the reaction is preferablycarried out at the temperature ranging from 0 C. to reflux temperatureof a solvent employed. The reaction period will depend mainly upon thereaction temperature and a kind of the reductan't and may vary fromabout hours to hours.

The compound (XX) may be prepared by contacting the compound (XIX) withan oxidizing agent in the presence of a solvent. As the oxidizing agent,there may be preferably employed chromic compounds, e.g., chromic acid,chromic anhydride, chromic acid-pyridine complex, sodium bichromate,potassium bichromate; halogenoamides, e.g., N-bromoacetamide,N-chlorobenzenesulfonamide; halogenoimides, e.g., N-bromosuccinirnide,N-bromophthalimide; aluminum alkoxides, e.g., aluminum tertbutoxide,aluminum isopropoxide; dimethyl sulfoxide-dicyclohexylcarbodiimide; anddimethyl sulfoxidc-acetic anhydride. As the solvent, there may beemployed any solvent without limitation that would not have an effect onthe reaction, but a preferable solvent is different depending upon theoxidizing agent. When chromic acids are employed, there may bepreferably employed carboxylic acids, e.g., acetic acid, a mixture of acarboxylic acid and a carboxylic acid anhydride, e.g., aceticacid-acetic anhydride; halogenohydrocarbon, e.g., methylene chloride,chloroform and carbon tetrachloride. When organic active halides areemployed, there may be preferably employed an aqueous organic solvent,for example, aqueous tertbutanol, aqueous acetone and aqueous pyridine.When aluminum alkoxides are employed, there may be preferably employedaromatic hydrocarbons, for example, benzene, toluene and xylene. In thiscase, it is preferable to employ, as a hydrogen acceptor, an excessamount of ketones, for example, acetone, methyl ethyl ketone,cyclohexanone and it is necessary to remove water completely from thereaction system. When dimethyl sulfoxide-dicyclohexylcarbodiimide ordimethyl sulfoxide-acetic anhydride is employed, there may be preferablyemployed an excess amount of the dimethyl sulfoxide without employmentof other solvents. When dimethyl sulfoxide-dicyclocarbodiimide isemployed, there is employed, as usual, a catalytic amount of acids,e.g., phosphoric acid, acetic acid, trifluoroacetic acid. As theoxidizing agent, there may be most preferably employed chromic acids,especially chromic acid-pyridine complex. The reaction temperature isnot critical, but it is desirable to carry out the reaction at lowtemperatures in order to control side reactions. It is preferably from30 C. to room temperature, most preferably from 0 C. to roomtemperature. The reaction period will depend mainly upon the reactiontemperature and a kind of the oxidizing agent and may vary from severalminutes to one hour.

In the process mentioned above the compound (II) can be produced asracemic mixtures and the racemic mixtures can be resolved at appropriatestages by methods well known in the art, whereupon subsequent productsmay be obtained as the corresponding optically pure isomers. In theabove schema both the optical isomer and the racemic forms are depictedby a single representation. But it should not be considered to limit thescope of the disclosure. Prostaglandin F10: [9a, 15a-trihydroxyprost-13(trans)-enoic acid] can be prepared from the 2-formylcyclopentanederivative (XX) by a known method. For instance, it can be prepared byreacting the compound (XX) with a Wittig reagent, e.g.,tri-n-butylphosphin-2-oxoheptylide, reducing the product with an alkalimetal boron hydride, e.g., sodium boron hydride and next hydrolyzing theproduct with an acid, e.g., acetic acid and, if necessary, subsequentlywith an alkali, e.g., potassium hydroxide.

On each step mentioned above, the reaction product may be recovered fromthe reaction mixture and purified by conventional means, for example,column chromatography and thin-layer chromatography. The followingpreparations and example are given for the purpose of illustration ofthis invention.

PREPARATION 1 Benzyl 3-oxo-9-ethoxycarbonylnonanoate (V) To 250 ml. ofanhydrous ether is added 3.76 g. of granulated metallic sodium and tothe mixture is added dropwise 32 g. of benzyl acetoacetate underice-cooling and stirring over one hour. After completion of theaddition, the mixture is further stirred at room temperature for 4hours. To the mixture is added dropwise 31 g. ofl-ethoxycarbonylheptanoyl chloride little by little under ice-cooling.After completion of the addition, the mixture is stirred at roomtemperature for 12 hours and subsequently refluxed for 30 minutes. Aftercompletion of the reaction, ice water is added to the reaction mixtureunder ice-cooling. The ether layer is separated, washed successivelywith 5% sulfuric acid and water and dried over anhydrous sodium sulfate.The ether is distilled off from the ether solution to give oils. Theoils are again dissolved in 450 ml. of anhydrous ether and into thesolution is passed ammonia gas for 30 minutes under ice-cooling andsubsequently for 2 hours at room temperature. Argon gas is passed intothe reaction mixture in order to put out the ammonia gas dissolved inthe reaction mixture. The ether layer is washed successively with a 3 Nhydrochloric acid solution and water and dried over anhydrous sodiumsulfate. The ether is distilled off from the ether solution. The oilyresidues are subjected to vacuum distillation and the fraction distilledat 180 C. (oil bath temperature) 10.1- 0.2 mm. Hg are removed. The oilyresidues are subjected to chromatography using neutral alumina (GradeIII, Woelm Co.) and eluted successively with some amount of hexane-ahexane solution containing 10% benzene and next successively with ahexane solution containing 20- 40% benzene. The eluates with the hexanesolution containing 20-40% benzene are collected and the solvent isdistilled off to give 13.3 g. of the oily desired product.

LR. (liquid film) v cmr z N.M.R. (CD01 r:p.p.m.

2.61 (5H, singlet, C -H 4.80 (2H, singlet,

5.83 (2H, quartette, 'CH CH OCO) 6.51 (2H, singlet,

Q-omo c 01120 0-) 8.75 (3H, triplet, CH CH OCO) PREPARATION 22-methoxy-2-methoxycarbonylmethyl 4benzyloxycarbonyl-S-(6-ethoxycarbonylhexyl) 2,3 dihydrofuran (VII) andmethyl 3-methoxy-S-benzyloxycarbonyl-6-oxo-12-ethoxycarbonyldodeca-Z-enoate (VHI) To 100 ml. of dry benzene areadded 16.166 g. of benzyl 3-oxo-9-ethoxycarbonylnonanoate and 1.1 g. ofgranulated metallic sodium and the mixture is stirred at roomtemperature overnight. To the mixture is added 9 g. ofmethyl-4-bromo-3-methoxy-2-butenoate and the mixture is refluxed for4.25 hours. After completion of the reaction, the reaction mixture iscooled and Washed successively with a dilute sulfuric acid solution andWater and dried over anhydrous sodium sulfate. The solvent is distilledOE and the residues are subjected to column chromatography using 200 g.of neutral alumina (Grade III, Woelm Co.) and eluted successively withsome amount of hexane-a hexane solution containing 8% benzene and nextwith a hexane solution containing 10% benzene. The eluates with thehexane solution containing 10% benzene are collected and the solvent isdistilled ofl? to give 1.548 g. of 2-methoxy-2-methoxycarbonylmethyl-4-benzyloxycarbonyl--(6 ethoxycarbonylhexyl)-2,3-dihydrofuran as oil. Theelution with a hexane solution containing benzene is further continuedto give 1.623 g. of a mixture of 2-methoxy-2-methoxycarbonylmethyl-4-benzyloxycarbonyl-S-(6-ethoxycarbonylhexyl) 2,3 dihydrofuran and methyl3-methoxy-5-benzyloxycarbonyl- 6-oxo-l2-ethoxycarbonyldodeca-2-enoate asoil. Furthermore the elution with a hexane solution containing l0 20%benzene is continued to give 6.975 g. of methyl 3-methoxy-S-benzyloxycarbonyl 6 oxo 12 ethoxycarbonyldodeca-Z-enoate asoil.

12 2-methoxy-2-methoxycarbonylmethyl 4benzyloxycarbonyl-5-(6-ethoxycarbonylhexyl)-2,3-dihydrofuran.

I.R. (liquid film) v cmr z 1645, 1700, 1738. N.M.R. (CDCI 'r:p.p.m.

2.64 (5 H, singlet, CH 4.83 (2H, singlet, C H CH OCO-) 5.88 (2H,quartette, CH CH OCO) 6.32 3H, singlet, CH OCO-) 6.70 (3H, singlet, CHO-) 8.76 (3H, triplet, OH CH 0CO-) Methyl3-methoxy-5-benzyloxycarbonyl-6-oxo-12- ethoxycarbonyldodeca-Z-enoate1R. (liquid film) v cm- 1630, 1712, 1741. N.M.R. (CD013) 1-:p.p.m.

2.67 (5H, singlet, C H 4.82 (2H, singlet, C H CH OOO) 4.95 (1H, singlet,

CHaOCOC=CCHz-) H CH;

6.33 (3H, singlet, CH OCO-) 6.50 (3H, singlet, CH 0 PREPARATION 3 Methyl3,6-dioxo-S-benzyloxycarbonyl-12-ethoxycarbonyldodecanoate (IX) In 5 m1.of chloroform is dissolved mg. of methyl 3methoxy-S-benzyloxycarbonyl-6-oxo-l2-ethoxycarbonyldodeca-Z-enoate andto the solution is added 15 drops of trifluoroacetic acid and thesolution is stirred at room temperature for 2 hours. After completion ofthe reaction, water is added to the reaction mixture. The mixture isextracted with ether. The ether layer is separated, washed with waterand dried over anhydrous sodium sulfate. The solvent is distilled off togive 105 mg. of the desired product as oil.

I.R. (liquid film) v cmr z N.M.R. (CDCI 'r:p.p.m.

2.67 (5H, singlet, C H e-) 4.85 (2H, singlet, C H CH OCO-) 5.89 (2H,quartette, CH CH OCO-) 6.30 (3H, singlet, CH 0CO) 8.78 (3H, triplet, CHCH OCO) PREPARATION 4 Methyl 3,6-dioxo-5-benzyloxycarbonyl-12-ethoxycarbonyldodecanoate (IX)2-methoxycarbonyl-3-(6-ethoxycarbonylhexyl)-4-benzyloxycarbonylcyclopentenone(X) In 20 ml. of absolute methanol is dissolved 505 mg. of methyl3,6-dioxo-S-benzyloxycarbonyl 12 ethoxycarbonyldodecanoate and to thesolution is added 400 mg. of potassium bicarbonate. The mixture isstirred at room temperature for 2 hours under heating at intervals.After completion of the reaction, the reaction mixture is diluted withwater and made alkaline by addition of acetic acid and extracted withether. The extract is washed with wais distilled off from the extract.The residues are subjected to column chromatography using g. of silicagel and eluted with some amount of benzene and next successively withbenzene-a benzene solution containing 1% ether. The eluates withbenzene-a benzene solution containing 1% ether are collected and thesolvent is distilled olf to give 280 mg. of the desired product as oil.

I.R. (liquid film) v cmr z 700, 750, 1630, 1735, 3300-3500. N.M.R. (CDCl1-:p.p.m.

@omoo o- 5.87 (2H, CH CH OCO'-) 6.16 (3H, CH OCO) 8.75 (3H, CH CH OCO)PREPARATION 6 2-methoxycarbonyl-3-(6-ethoxycarbonylhexyl)-4benzyloxycarbonylcyclopentenone (X) To a mixture of 0.34 g. ofgranulated metallic sodium and 20 m1. of 1,2-dimethoxyethane is addeddropwise 5 g. of benzyl 3-oxo9-ethoxycarbonylnonanoate at roomtemperature. After the metallic sodium is disssolved, 1.4 g. of methyl-bromoacetoacetate in ml. of 1,2-dimethoxyethane is added dropwise tothe solution. The mixture is stirred at room temperature for 3 hours.After completion of the reaction, 100 ml. of ice water is added to thereaction mixture. The mixture is extracted with hexaneether (1:1) toremove the unreacted starting material. To the aqueous layer is added10% hydrochloric acid under ice-cooling to adjust to pH 3 and theaqueous layer is extracted with ethyl acetate. The extract is washedwith water and dried over anhydrous sodium sulfate and the solvent isdistilled olf to give 2.161 g. of the desired product as oil.

The infrared absorption spectrum and nuclear magnetic resonance spectrumof the product are the same as those of the product obtained inPreparation 5.

PREPARATION 7 2 fi-methoxycarbonyl-3 a- (6 -ethoxycarb onylhexyl)4ctcarboxylcyclopentanone (II) In 40 ml. of methanol is dissolved 249mg. of 2-methoxycarbonyl-3-(6 ethoxycarbonylhexyl) 4benzyloxycarbonylcyclopentenone and to the solution is added 300 mg. of5% palladium on charcoal. The mixture is subjected to catalyticreduction. The reduction is completed when approximately 25 ml. ofhydrogen gas is absorbed. After completion of the reaction, the catalystis removed from the reaction mixture and the solvent is distilled off.The residues are subjected to column chromatography using 4 g. of silicagel washed with an acid and eluted successively with some amount ofbenzenea benzene solution containing 2% ether and next with a benzenesolution containing 5% ether. The eluates with the benzene solutioncontaining 5% ether are collected and the solvent is distilled off togive 127 mg. of the desired product as oil.

LR. (liquid film) v cmf t 1700, 1740, 1750, 3200 (broad). N.M.R. (CDClT: .m.

2.06 (1H, singlet, COOH) 5.88 (2H, quartette, CH CH OCO) 6.23 (3H,singlet, CH OCO) 8.74 (3H, triplet, CH CH OCO-) 14 PREPARATION s1a-acetoxy-2,8-methoxycarbonyl-3u-(6-ethoxycarbonylhexyl)4a-carboxycyclopentane (XII) In 4 ml. ofpyridine is dissolved 652 mg. of lwhydroxy- 2fl-methoxycarbonyl-3a-(6ethoxycarbonylhexyl) 4acarboxycyclopentane and to the solution is added2 ml. of anhydrous acetic acid. The mixture is left to stand for 10hours at 0 C. and subsequently for 3 hours at room temperature afteraddition of water. The reaction mixture is diluted with water, madeacidic by addition of dilute hydrochloric acid and extracted with ether.The extract is washed with water and dried over anhydrous sodium sulfateand the solvent is distilled 0E. The residues are subjected to columnchromatography using 7 g. of silica gel and eluted with some amount ofbenzene and next successively with a benzene solution containing 15%ether. The eluates 'with the benzene solution containing 15% ether arecollected and the solvent is distilled oil. to give 590 mg. of thedesired product as oil.

1720, 1750, 3250 (broad). N.M.R. (CDCl -r:p.p.m.

1.48 (1H, broad singlet, COOH) 4.71 (1H, multiplet,

5.85 (2H, quartette, CH CH OCO-) 6.27 (3H, singlet, CH OCO) 7.95 (3H,singlet, CH COO-) 8.73 (3H, triplet, CH CH OCO) PREPARATION 91a-acetOXy-ZB-methoxycarbonyl-3t:-6-ethoxycarbonylhexyl)-4a-chlorocarbonylcyclopentane (XIII) In 10 ml. ofbenzene is dissolved 550 mg. of la-acetoxy- 25 methoxycarbonyl 3oz (6ethoxycarbonylhexyl)- 4a-carboxycyclopentane and to the solution isadded 3 ml. of oxalyl chloride. The mixture is refluxed for 3 hours and,after addition of 5 ml. of oxalyl chloride, left to stand overnight atroom temperature. After completion of the reaction, the solvent and anexcess of the reagent are distilled off from the reaction mixture togive the desired product as oil. The product thus obtained may beemployed without purification in the next reaction.

PREPARATION 10 1wacetoxy-Zfi-methoxycarbonyl-3a-( 6-ethoxycarbonylhexyl)4a-acetylcyclopentane (XIV) To a dimethyl cuprous lithium ether solutionprepared by adding 13.24 ml. of a 0.8 M solution of methyl lithium inether to a solution of 1.018 g. of cuprous iodide in 15 ml. of ether, isadded dropwise at 78" C. a solution of the1a-acetoxy-ZB-methoxycarbonyl-3a-(6-ethoxycarbonylhexyl)-4a-chlorocarbonylcyclopentaneobtained in Preparation l0 dissolved in 5 ml. of ether. After completionof the addition, the reaction mixture is left to stand for 20 minutes,diluted with 5 ml. of methanol at 78 C. and neutralized by addition ofaqueous acetic acid. The mixture is extracted with ether at 0 C. Theextract is washed with water and dried over anhydrous sodium sulfate andthe solvent is distilled off. The residues are subjected to columnchromatography using 10 g. of silica gel and eluted with some amount ofbenzene and next successively with a benzene solution containing 1-5%ether. The eluates with the benzene solution containing 1-5% ether 15are collected and the solvent is distilled off -to give 330 mg. of thedesired product as oil.

LR. (liquid film) v cmf N.M.R. (CDCl :p.p.m.

4.74 (1H, multiplet PREPARATION 11 1a,4u-diacetoxy-2fl-methoxycarbonyl-3a- 6-ethoxycarbonylhexyl cyclopentane (XV) To a solution of 309 mg. of1a-acetoxy-2/i-methylcarbonyl 3oz (6 ethoxycarbonylhexyl) 4ozacetylcyclopentane and 1.85 g. of disodium hydrogenphosphate in 5 ml. ofmethylene chloride is added dropwise under icecooling a methylenechloride solution of pertrifluoroacetic acid prepared by 0.135 ml. of90% hydrogen peroxide, 3 ml. of methylene chloride and 0.85 ml. ofanhydrous trifluoroacetic acid. After completion of the addition, themixture is stirred at room temperature for 45 minutes. After completionof the reaction, the reaction mixture is diluted with water andextracted with ether. The extract is washed successively with water,aqueous sodium iodide, aqueous sodium thiosulfate and water and driedover anhydrous sodium sulfate. The solvent is distilled olf to give 312mg. of the desired product as oil.

I.R. (liquid film) v cmr z 4.70 (2H, multiplet,

oooon. H

ooocri. H

5.80 (2H, quartette, CH CH OCO) 6.22 3H, singlet, CH OCO-) 7.89 (3H,singlet, CH COO--) 7.91 (3H, singlet, CH COO) 8.69 (3H, singlet, CH CHOCO') PREPARATION l2 1a,4ct-dihydroxy-2fl-methoxycarbonyl-3u-(6-ethoxycarbonylhexyl)cyclopentane(XVI) To a solution of 4.151 g. of1u,4a-diacetoxy-2,8-methoxy-carbonyl-3u-(6-ethoxycarbonylhexyl)cyclopentanein 100 ml. of absolute ethanol is added 7.5 g. of potassium carbonateand the mixture is stirred at 45 C. for one hour. After completion ofthe reaction, acetic acid is added to the reaction mixture and thesolvent is distilled 011?. The residues are extracted With ether and thesolvent is distilled oif from the extract. The residues are subjected tocolumn chromatography using 35 g. of silica gel and eluted withsuccessively some amount of benzene-a benzene solution containing 18%ether and next successively with a benzene solution containing 20-30%ether. The eluates with the benzene solution containing 2030% ether are16 collected and the solvent is distilled oif to give 1.264 g. of thedesired product as oil.

I.R. (liquid film) v cmf z N.M.R. (CDCl 1-:p.p.m. 5.70 (2H, broadsinglet,

5.80 (2H, quartette, CH CH OCO--) 6.30 (3H, singlet, CH OCO) 8.70 (3H,triplet, CH CH CO) PREPARATION 13 1u,4a-di Z-tetrahydropyranyloxy-2/8-methoxycarb0nyl- 3 u-( 6-ethoxycarbonylhexyl) cyclopentane (XVII)In 6 ml. of benzene is dissolved 1.429 g. of 1a,4oz-dihydroxy 2pmethoxycarbonyl 3a (6 ethoxycarbonylhexyl)cyclopentane and to thesolution is added 5 ml. of dihydropyran and a small amount of picricacid. The mixture is left to stand for 11 hours under ice-cooling andand subsequently at ---15 C. overnight. After completion of the reactionthe solvent is distilled off from the reaction mixture. The residues aresubjected to column chromatography using 10 g. of neutral alumina (GradeIII, Woelm Co.) and eluted with benzene. The eluates are collected andthe solvent is distilled off to give 2.192 g. of the desired product asoil.

I.R. (liquid film) v cmr N.M.R. (CDCl -r:p.p.m. 5.45 (2H, broad singlet,

5.81 (2H, quartette, CH CH OCO) 6.31 and 6.32 (3H, CH OCO-) 8.1 (3H,triplet, CH CH OCO) PREPARATION 14 1 0:,4a-di Z-tetrahydropyranyloxy-2l3-hydroxymethyl- 3 a- (6-ethoxycarbon'ylhexyl cyclopentane (XIX) To asolution of 635 mg. of 111,40: di(2 tetrahydropyranyloxy) 213methoxycarbonyl 3a (G-ethoxycarbonylhexyl)cyclopentane in 10 ml. ofabsolute ethanol is added 1.2 g. of sodium boron hydride and the mixtureis stirred at 0 C. for 25 hours. After completion of the reaction, asmall amount of acetic acid is added to the reaction mixture is order todecompose the excess of sodium boron hydride. The mixture is dilutedwith water and extracted with ether. The extract is washed with waterand dried over anhydrous sodium sulfate. The solvent is distilled oil?from the extract. The residues are subjected to column chromatographyusing 2 g. of neutral alumina (Grade 111, Woelm Co.) and elutedsuccessively with some amount of hexane-'a hexane solution containingbenzene and next successively with a hexane solution containing 40-60%benzene. The eluates with the hexane solution containing 40-60% benzeneare collected and the solvent is distilled oil to give mg. of thestarting material. The elution is continued using successivelybenzene--a benzene solution containing 30% ethyl acetate to give 149 mg.of the desired product as oil.

LR. (liquid film) v cmr N.M.R. (CDCl r:p.p.m. 5.30 (2H, broad singlet,

5.80 (2H, quartette, CH CH OCO) 8.1 (3H, triplet, CH CH OCO-)PREPARATION 15 10:,4a-di (Z-tetrahydropyranyloxy) -2 3-methoxycarbonyl-3 a- (6-carboxyh exyl cyclopentane (XVIII) In 70 ml. of 30% aqueousmethanol containing potassium carbonate is dissolved 3 g. of 1a,4udi(2-tetrahydropyranyloxy) 218 methoxycarbonyl 3a (6ethoxycarbonylhexyl)cyclopentane and the solution is stirred at roomtemperature for 4 hours. After completion of the reaction, the reactionmixture is diluted with water and hexane is added to the mixture. Thehexane layer is separated and washed with water and dried over anhydroussodium sulfate. The solvent is distilled off to give 1.521 g. of thestarting material. The aqueous layer is made acidic by addition ofacetic acid and extracted with ethyl acetate. The extract is washed withwater and dried. The solvent is distilled 01f to give 1.432 g. of thedesired product as oil.

LR. (liquid film) u cmr z N.M.R. (CDCl 'r:p.p.m.

5.30 (2H, broad singlet 6.32 (3H, singlet, CH OCO-) PREPARATION 161a,4a-di 2-tetrahydropyranyloxy) -2;3-hydroxymethyl- 3ot(6carboxyhexylcyclopentane (XIX) In 100 ml. of anhydrous tetrahydrofuran is dissolvedthe potassium salt prepared from 1.4 g. of 111,40; di(2-tetrahydropyranyloxy) 2B methoxycarbonyl 3oz (6-carboxyhexyl)cyclopentane and 330 mg. of potassium bicarbonate and,after addition of 1.4 g. of lithium boron hydride, the mixture isrefluxed for 15 hours. After completion of the reaction, ice water andsubsequently a small amount of dilute hydrochloric acid are added to thereaction mixture to decompose the excess of lithium boron hydride. Themixture is extracted with ether. The extract is washed with water anddried over anhydrous sodium sulfate and the solvent is distilled off.The residues are subjected to column chromatography using 7 g. of silicagel and eluted some amount of hexane and next successively withbenzene-a benzene solution contained 30% ethyl acetate. The eluates withthe benzene solution containing 30% ethyl acetate are collected and thesolvent is distilled off to give 995 mg. of the desired product as oil.

LR. (liquid film) v cmr 1700, 3300-3400. N.M.R. (CDCl -r:p.p.m.

5.30 (2H, broad singlet,

18 PREPARATION 17 111,40; di(2 tetrahydropyranyloxy)-2p-formyl-3a-(6-ethoxycarbonylhexyl)cyclopentane (XX) To a solution of 1a,4a di(2tetrahydropyranyloxy)- 2 8 hydroxymethyl 3a (6ethoxycarbonylhexyl)cyclopentane in 25 ml. of methylene chloride isadded 2.5 g. of anhydrous chromic acid-pyridine complex under icecoolingand the mixture is stirred for 15 minutes. After completion of thereaction, the reaction mixture is extracted with ether. The extract iswashed with water and dried over anhydrous sodium sulfate. The solventis distilled off to give 123 mg. of the desired product as oil.

I.R. (liquid film) v cmr' z The absorption caused by the hydroxy groupwas not observed.

PREPARATION 18 Preparation of prostaglandin Fla from 111,411di(2-tetrahydropyranyloxy) 2p formyl 3a(6-ethoxycarbonylhexyl)cyclopentane (XX) 9a,l1a,15a trihydroxyprost 13(trans) epoic acid (prostaglandin F (1) To a solution of 123 mg. of10:,411 di(2 tetrahydropyranyloxy) 2/3 formyl 3a (6ethoxycarbonylhexyl)cyclopentane in 5 ml. of ether is added a solutionof 168 mg. of tri n butylphosphin 2 oxoheptylide in 1.5 ml. of ether andthe mixture is stirred at room temperature for 17 hours. Aftercompletion of the reaction, the solvent is distilled oil from thereaction mixture. The residues are subjected to column chromatographyusing 3 g. of neutral alumina (Grade 111, Woelm Co.) and elutedsuccessively with some amount of hexanea hexane solution containing 8%benzene and next with a hexane solution containing 10% benzene. Theeluates with the latter solvent are collected and the solvent isdistilled off to give oils. The oils are further subjected to columnchromatography using 3 g. of silica gel and eluted with some amount ofbenzene and next successively with a benzene solution containing 1-5%ether. The eluates with the henzene solution containing 15% ether arecollected and the solvent is distilled off to give 138 mg. of ethyl9a,11ot di(2 tetrahydropyranyloxy) 15 oxoprost-13(trans)- enoate.

LR. (liquid film) v cmr z N.M.R. (CDCl -r:p.p.m.

2.8-4.2 (2H, multiplet,

5.39 (2H, broad, singlet,

(2) To a solution of 270 mg. of ethyl 9oz,11oz-di(2-tetrahydropyranyloxy) 15 oxoprost 13(trans)-enoate in 20 ml. of methanolis added 500 mg. of sodium boron hydride under ice-cooling and themixture is stirred at 0 C. for one hour. After completion of thereaction, ice Water and subsequently acetic acid are added to thereaction mixture to decompose the excess of sodium boron hydride. Themixture is extracted with ether and the extract is washed with water anddried over anhydrous sodium sulfate. The solvent is distilled off fromthe extract.

5.80 (2H, quartette, CH CH OCO-) 5.90 (2H, broad singlet,

The residues are subjected to column chromatography using 4.5 g. ofsilica gel and eluted successively with some amount of benzene-a benzenesolution containing 3% ether and next successively with a benzenesolution containing 5% etherethyl ether. The eluates with the ben- 5zene solution containing 5% ether-ethyl acetate are collected and thesolvent is distilled oil to give 144 mg. of ethyl9a,11u-di(Z-tetrahydropyranyloxy) 15 hydroxyprost-13 (trans) -enoate.

no H

LR. (liquid film) v cmr z 10 970 (trans double bond), 3470. 3.73 (3H,triplet, CH CH OCO) (CDC13) F Mass spectrum M -H Oz 352.

4.40 (2H, multlplet,

15 (4) In 5 ml. of 30% aqueous methanol containing 2% potassiumhydroxide is dissolved 60 mg. of ethyl 90a, 11a,l5a-trihydroxyprost-l3(trans)-enoate and the solution is stirred at roomtemperature and subsequently at 50 C. for 3 hours. After completion ofthe reaction, a small amount of acetic acid is added to the reactionmixture and the solvent is distilled off under reduced pressure. Theresidues are dissolved in ethyl acetate-ether (1:1) and washed with asmall amount of water and the solvent is distilled off. To the residuesis added an ether-hexane solution to crystallize. The crude crystals arerecrystallized from ethylacetate-hexane to give 23 mg. of pure 9a,lla,l5a-trihydroxyprost-13(trans)-onoic acid (prostaglandin Fla) melting at78-79.5 C.

I.R. (melt) v 2 960 (trans double bond), 1710, 3350.

N.M.R. (CDCl r:p.p.m. 4.55 (2H, multiplet,

(3) In a mixture of 1 m1. of tetrahydrofuran, 10 ml. of acetic acid and5 ml. of water is dissolved 124 mg. of ethyl 941,110: di(2tetrahydropyranyloxy)-1S-hydroxyprost -13 (trans) enoate and thesolution is stirred at 30-40 C. for 2 hours. After completion of thereaction, the reaction mixture is diluted with water and extracted withethyl acetate-ether (1:1). The extract is Washed with water and driedover anhydrous sodium sulfate and the solvent is distilled 01f to give110 mg. of oils. The oils are subjected to column chromatography using 2g. of silica gel and eluted successively with some amount of benzene-abenzene solution of 10% ethyl acetate and next successively with abenzene solution containing -30% ethyl acetate. The eluates with thebenzene solution containing 20-30% ethyl acetate are collected and thesolution is distilled oif to give 20 mg. of ethyl9a,11a,15/3-trihydroxyprost 13 (trans) enoate as oil. The elution iscontinued using successively a benzene solution containing 30-40% ethylacetate to give 50 mg. of a mixture of ethyl 9a,1la,15p-trihydroxyprost13 (trans)-enoate and ethyl 9a,l1a,15oc trihydroxyprost 13 (trans)enoate as oil.

6.00 (3H, broad, singlet,

The elution is further continued using successively a ben- Ito H zenesolution containing 60-80% ethyl acetate to give 28 mg. of ethyl9a,11ot,l5ot trihydroxyprost 13 (trans)- enoate as oil.

Ethyl 9a,11u,1SB-trihydroxyprost-13-(trans)-enoate. Ho H 110' H I.R.(CHCl v cmfh 970 (trans double bond), 1730, 3400. N.M.R. (CDCl T:p.p.m.

4.42 (2H, multiplet,

Mass spectrum MH O: 338.

Example H 1a-hydroxy-2 3-methoxycarbonyl-3a(6-ethoxycarbonyl- Hhexyl)-4u-carboxycyclopentane (I) b d 1 In a mixture of 30 ml. ofethanol and 7.5 ml. of water (2H, ma 5mg at, .55 is dissolved 1.221 g.of 2-fl-methoxycarbonyl-3a-(6-ethoxycarbonylhexyl)-4a-carboxycyclopentanone and to the 0 H solution is added 880 mg. ofsodium bicarbonate. To the mixture is added 400 mg. of sodium boronhydride under ice-cooling and the mixture is left to stand for 15minutes.

After completion of the reaction, Water and subsequently H 6- H a smallamount of acetic acid are added to the reaction 5.81 (2H, quartette, CHCH OCO) 8.73 (3H, triplet, CH CH OCO) Ethyl9a,11a,15a-trihydroxyprost-13-(trans)-enoate.

LR. (CHCl v cmr' 970 (trans double bond), 1730, 3400.

mixture in order to decompose the excess sodium boron hydride. Themixture is made acidic by addition of concentrated hydrochloric acid andextracted with ether. The extract is washed with water and dried overanhydrous sulfuric acid. The solvent is distilled oil. The residues thusobtained are subjected to column chromatography using 12 g. of silicagel washed with an acid and eluted with some amount of benzene and nextsuccessively with a benzene solution contain 10-20% ether. The eluateswith the benzene solution containing 1020% ether are collected and thesolvent is distilled off to give 730 mg. of the desired product as oil.

I.R. (liquid film) v cmr' z 1715, 1742, 3250, 3480.

21 N.M.R. (CDCI 1-:p.p.m.

3.28 (2H, broad singlet, COOH and --OH) 5.58 (1H, singlet,

UCOOR wherein R and R may be the same or different and each representsan alkyl group having 1-6 carbon atoms or its optical isomer or theracemic mixture thereof.

2. 1a hydroxy 2/8 methoxycarbonyl-3a-(6-ethoxy- 25carbonylhexyl)-4a-carboxycyclopentane.

22 3. A compound having the formula goon ' ---(CH;)6CO0R 1-00 0R whereinR and R may be the same or different and each represents an alkyl grouphave 1-6 carbon groups, or its optical isomer or the racemic mixturethereof.

4. A compound of claim 3 comprising ZB-methoxycarbonyl 3a (6ethoxycarbonylhexyl)-4a-carboxycyclo pentanone.

References Cited House, Modern Synthetic Reactions, pp. 23-31 (1965).Katsube et al., Asi. Biol. Chem., 35, 1828 (1971).

ROBERT GERSTL Primary Examiner US. Cl. X.R.

260345.7, 345.8, 345.9, 347.5, 404, 410 R, 413, 464, 465 D, 468 D, 476R, 483, 488 R, 514 D, 557 R I UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 806.535 f Dated Aprilfl23, 1974 Inventor(s)KIYOSHI SAKAI et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, line '50: replace with Column 2, line 28: I delete"2formylcyclopentane derivatives I having the formula" Column 8, line23: replace "perluric" with perlauric--- Column 9, line 36: after"sodium bicarbonate", insert a comma Column 11, lines 29-41: rewrite asfollows:

--4.80. (2H, singlet, @C IEQOCO- 5.83 (2H, quartette, cH cg oco- 6.51(2H, singlet, cr1 ococg co- 8.75 (3H, triplet, c cH oco- Column 12, Ilines 6-12: rewrite as follows:

. --2;64 (5H, singlet, C fi 4.83. (2H, singlet, C H C OC0 FORM l e-1050(IO-69) V USCOMM-DC scan-P09 l-LS. GOVEWNMI!" I'Il'fl'lnfi O FICE: Hi90-355-334.

UNl ED STATES PATENT OFFICE PAGE 2 CERTIFICATE OF CORRECTION Patent No.3,806,535 Dated April 23, 1974 Inventor(s) KIYOSHI SAKAI et al It iscertified that error appears in the aboveiden'tified patent and thatsaid Letters Patent are hereby corrected as shown below:

5.88 (23, qua-rtette, crl c oco- 6.32 (B l 1, singlet, CAI3OCO 6.70 (3H;singlet, CE3O- 8.76 (5H, triplet, c l cll oco- Column 12, lines 1.8-25:I rewrite as follows:

---2'.67 (5H, singlet, 0 5

4.82 (2H, singlet, c H C Oc0- 4.95 -(lH, singlet, CH OCOC I=( ZCH I OCH35.89 (2H, quartette, CH C OCO- .PAGE 3 UNITED STATES PATENT OFFICE.

CERTIFICATE OF CORRECTIGN Patent No. 3,806,535 Dated April 23, 1974Inventor-(s) 'KIYOSH'I SAKAI et al It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

6.{30-.(3H, singlet, CI-3OCO 8,7 8 (3s,- triplet, cg cH oco- Colurr m13, lines 13-24: rewrite as follows:

J 1 v 4.80 (2H, @cgpco- 5.87 (2H, cn cg ocol 6. 16 (in, cg oco- 8.75(23H, cg cn oco- Column 13, lines 72-75: rewrite as followsi -2.06 (1H,singlet, 40% I 5.88 (2H, quartette, CH C Ii OCO 6.23 'V(3H, singlet, cI3 oco- 8.74 (3H, triplet, cg cH oco- Column 14, linesi'24-4O: rewriteas follows:

--l.48 (1H, broad singlet, -COO DRM PO-IOSO (IO-59) uscoMM-oc scan-pea nu.s. covznun uar "nu-mo omc: I n a PAGE 4 UNITED STATES PATENT OFFICECE-RTIFICA'IE 0F CORRECTION Patent No. 3,806,535 Dated April 23, 1974Inventor(s) KIYOSHI SAKAI et al It is certified that error appears inthe above-identified patent arTrI that said Letters Patent are herebycorrected as shown below:

0... a 4.7l (1H, multiplet,

I i 0 iv OCOCH3 5. 85 (2H, quartette, CH3C2OCC 6.27. Y(3H, singlet, cgoco- 7.95, 3 singlet, cg c oo- 8.73 (311, triplet, cg cH oco- Column 15,lines 6-20: rewrite as follows:

.4,.7 L (lH, multiplet H 5.86 (2H, quartette, cH c 0co- 5.30 (3H,singlet, cg oc o- 7.85 (3H, singlet, C3CO 7.95 (3li, singlet, c coo-8.56 (:3H, triplet, c cH 0coi Column 15, lines 44-57: rewrite asfollows:

F OR-d PO-! 050 (10-69) USCOMM-DC 80376-1 59 I .5. GOVEIN'OiNY PIINYINGOFFICE I95 9-3533L PAGE 5 UNITED STATES PATENT OFFICE "CERTIFICATE OFCORRECTION i Patent No.- 3,806,535 3 Dated A ril 23, 1974 Inventor-(s)KIYOSHI SAKAI .et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

QQQ -4.70 (2H, multiplet,

If We 0602:111

5.80 (2H, quartette, CH CI OCO 6.22 (3H, singlet, .C H OCO 7.89 (3H,singlet, cg coo- 7.91 (3H, singlet, C I;I CO0 8.69 (3H, singlet, CI CHOCO Column 16, lines 63-20: rewrite as follows:

. g 3 OH v ---5.70 (2H, broad singlet,

5.80 (2H, quartette, C CH OCO 6.30 (3H, singlet, C OCO- 8.70 (3H,triplet, cg cn co- Column 16, lines 41-52: rewrite as follows:

- CERTIFICATE OF CORRECTION Patent No. 3,806,535 Dated Agril 23,1974

Inventor(s) KIYOSHI SAKAI et el It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

, Column 17, lines 6-14: rewrite as follows:

---5.30 (2H, broad singlet,

' I 5.80 (2H, quartette, cH c rg oco- 8.71 (3H, tri 1et, cg cH' ocoColumn 17, lines 36-43: rewrite as follows:

-5.30 (2H, broad singlet 0 6.32 3H, singlet, C E OCO (lolumn 17, lines70-75: rewrite as follows:

-5.30 (2H, broad singlet, ll

ORM PC4050 (IO-69) uscoMM-oc man-ps9 0.5. GOVERNMENT PI IOUHG OFHC! I96!0-156-336.

PAGE 7 NITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,806,535 Dated April 23, 1.974

Inventor(s) KIYOSHI SAKAI et al It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 18, lines 50-65: rewrite as follows --2.8-4.2 (2H, multiplet,

5.39 I (2H, broad, singlet,

Column 19, lines 13-18; rewrite as follows:

. QI-IIV --4.40 (2H, multlplet,

7 Column 19, lines 48-65: rewrite as follows:

-4.42 (2H, 'multiplet,

HO WW 5.80 (2H, broad singlet,

5.81 (2H, quartette, cH cg 0co- 8.73 '(BH, triplet, C'EI3CHZOCQ- Column19, line 72 Column 20, line 12: rewrite as follows:

. 4 58 (2H, multiplet PAGE'B UNITED STATES PATENT. OFFICE CERTIFICATE OFCORRECTION Patent No. 3,8064535 Dated" Agril 23, 1974- Inventor(s)KIYOSHI SAKAI et al It is certified; that; error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

5.80 (2 iqu arte tce, oH c5 oco- 13 5.90 (2H, :broad singlet,

- 2 HO 8.73 (3H, trlplet, C I CH OCO e M Column 20, lines 32-45! rewriteas follows:

--4.55 (2H, multiplet,

. HO Column 21, lines 2-10; rewrite as follows: w

-3.28 (2H, broad singlet, -C(3O I, am? -0 5.58 (1H, singlet, Q

5.85 (2H, quartetc e, CH C E I OCO Column 22, line 11: replace "have"with --having--- Signed and sealed this 21st day of, Janualy 1975.

(SEAL) Attest:

McCOY GIBSQN JR. C. MARSHALL DANN Attestlng Off1cer v Commissioner ofPatents FORM PO-IOSO (10-69) USCOMM DC Goa-W'Psg u.s. GOVERNMENT rnmnm;a ncc; l9! O-Jii-Jl.

